Kseplion

General characteristics. Structure:

Active agent: 100 mg of a paliperidon in 1 ml of suspension (156 mg of a paliperidon of palmitate are equivalent).

Excipients: polysorbate of 20 - 12 mg, a macrogoal 4000 (polyethyleneglycol 4000) – 30 mg, citric acid monohydrate – 5 mg, sodium hydrophosphate – 5 mg, dihydrophosphate sodium monohydrate – 2,5 mg, sodium hydroxide – 2,84 mg, water for injections – to 1 ml.

Pharmacological properties:

Pharmacodynamics.

Action mechanism.

Paliperidona palmitate is hydrolyzed to a paliperidon. The last is a tsentralnodeystvuyushchy active antagonist of preferential serotoninovy 5 HT2A-receptors, and also dopamine D2 receptors, adrenergic α1-and α2-receptors and H1-histamine receptors. Paliperidon does not communicate in skholinergichesky m receptors and with adrenergic β1-and β2-receptors. Pharmacological activity (+) and (-) enantiomer of a paliperidon quantitatively is also qualitatively identical.

It is supposed that the therapeutic effectiveness of drug at schizophrenia is caused by the combined blockade of D2 and 5-HT2A - receptors.

Pharmacokinetics.

Absorption and distribution Because of exclusively low solubility in water of a paliperidon palmitate after intramuscular introduction is slowly dissolved and soaked up in a system blood stream. After single intramuscular introduction concentration of a paliperidon in a blood plasma slowly increases, reaching a maximum in 13-14 days (median) after introduction to a deltoid muscle and 13-17 days after introduction to a gluteus. Release of substance is found in the 1st day and, at least, 126 days remain. Characteristics of release of active component and the scheme of a drug dosing Kseplion provide long maintenance of therapeutic concentration. After single introduction of a dose of 25 - 150 mg to a deltoid muscle the maximum concentration (Cmax) is on average 28% more, than after introduction to a gluteus. At the beginning of therapy administration of drug in a deltoid muscle helps to reach quicker therapeutic concentration of a paliperidon (150 mg in the 1st day and 100 mg for the 8th day), than introduction to a gluteus. After repeated injections the difference in influence is less obvious. The average relation of the maximum and equilibrium concentration of a paliperidon after introduction of 4 injections of drug Kseplion in a dose of 100 mg in a gluteus equaled 1,8, and after introduction to a deltoid muscle – 2,2. At doses of a paliperidon of 25-150 mg the area under a curve "concentration time" (AUC) of a paliperidon changed in proportion to a dose, and Cmax at doses more than 50 mg increased to a lesser extent, than in proportion to a dose.

The median of an elimination half-life of a paliperidon after administration of drug of Kseplion in doses of 25-150 mg fluctuated within 25 - 49 days.

After administration of drug (-) - the enantiomer of a paliperidon partially turns in (+) - an enantiomer, and AUC relation (+) - and (-) - enantiomer are made by about 1,6-1,8. In the population analysis the seeming volume of distribution of a paliperidon equaled 391 l; палиперидон contacts proteins of a blood plasma for 74%.

Metabolism and removal.

In a week after single oral administration of 1 mg of drug of a 14C-paliperidon with immediate release of active component with urine in not changed look 59% of the entered dose are removed; it indicates lack of essential metabolism of drug in a liver. About 80% of the entered radioactivity were found in urine and 11% - in Calais. 4 ways of metabolism of the drug in vivo are known, but any of them does not cause metabolism of more than 6,5% of the entered dose: dealkylation, hydroxylation, dehydrogenation, eliminating of benzizoksazolny group. Though the researches in vitro allow to assume a certain role of isoenzymes of CYP2D6 and CYP3A4 in metabolism of a paliperidon given about an essential role of these isoenzymes in metabolism of a paliperidon to in vivo is not present. The population pharmacokinetic analysis did not reveal noticeable distinction of clearance of a paliperidon after oral administration of drug by people with active and weak metabolism of CYP2D6. Researches with use of microsomes of a liver of the person of in vitro showed what палиперидон significantly does not inhibit metabolism of medicines isoenzymes of CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4 and CYP3A5.

In the researches in vitro палиперидон showed properties of substrate of a P-glycoprotein, and in high concentration - properties of weak inhibitor of a P-glycoprotein. There are no relevant data of in vivo, and the clinical importance of these data is not clear.

In general, concentration of a paliperidon in a blood plasma in the period of loading after intramuscular administration of drug of Kseplion lay in the same range, as after reception of a paliperidon of the prolonged action orally with release of active component in doses between 6 and 12 mg. The used scheme of loading of a paliperidon provides maintenance of concentration in this range even at the end of an interdose interval (the 8th and 36th day). After administration of drug Kseplion different patients had individual distinctions of pharmacokinetics of a paliperidon less, than after reception of a paliperidon of the prolonged action orally. Because of distinction of nature of change of a median of concentration of a paliperidon in a blood plasma at use of two drugs, it is necessary to show care at direct comparison of their pharmacokinetics.

Special categories of patients.

Abnormal liver function. Paliperidon is not exposed to essential metabolism in a liver. Though drug use Kseplion at patients with an abnormal liver function easy or moderate severity was not studied, at such abnormal liver functions dose adjustment is not required. In a research use of a paliperidon orally patients with an abnormal liver function of moderate severity (a class B on Chayldu-Pyyu) in a blood plasma had the same concentration of a free paliperidon, as at healthy volunteers. At patients with an abnormal liver function of heavy degree use of a paliperidon was not studied.

Renal failure. For patients with a renal failure of easy severity the dose of a paliperidon should be reduced; Kseplion is not recommended to apply at patients with a renal failure of moderate severity and heavy degree. Distribution of a paliperidon after a single dose in a tablet of a paliperidon of the prolonged action of 3 mg by patients with different extent of disturbance of functions of kidneys was studied. With reduction of the clearance of creatinine (CC) removal of a paliperidon was weakened: at disturbance of functions of kidneys of easy severity (KK of 50-80 ml/min.) - for 32%, at moderate severity (KK of 30-50 ml/min.) – for 64%, at heavy degree (KK of 10-30 ml/min.) – for 71% therefore AUC0-∞ increased in comparison with healthy volunteers respectively in 1,5, 2,6 and 4,8 times. Proceeding from a small amount of data on drug use Kseplion at patients with a renal failure of easy severity and from results of modeling of pharmacokinetics, the recommended load dose of a paliperidon for such patients makes 75 mg in the 1st and 8th day; after that monthly (each 4 weeks) enter 50 mg.

Elderly patients. The age in itself is not the factor demanding dose adjustment. However such correction can be required because of age reduction of KK.

Race. The population pharmacokinetic analysis of results of a research of a paliperidon for intake did not reveal distinction of pharmacokinetics of a paliperidon after administration of drug by people of different races.

Floor. Clinically significant distinctions of pharmacokinetics of a paliperidon at men and women are not found.

Influence of smoking on drug pharmacokinetics. According to researches with use of microsomes of a liver of the person of in vitro, палиперидон is not CYP1A2 substrate therefore smoking should not influence pharmacokinetics of a paliperidon. According to these data in vitro, the population pharmacokinetic analysis did not reveal distinction of pharmacokinetics of a paliperidon at smokers and not smoking people.

Indications to use:

Treatment of schizophrenia and prevention of a recurrence of schizophrenia.

Route of administration and doses:

At the patients never accepting палиперидон orally or рисперидон orally or parenterally before an initiation of treatment with drug Kseplion is recommended to check within 2-7 days portability of a paliperidon or risperidon orally.

It is recommended to begin treatment with drug Kseplion with a dose of 150 mg in the 1st day and 100 mg in 1 week (both injections in a deltoid muscle). The maintenance dose of 75 mg is recommended once a month; the effect can be observed from reception of high or smaller doses, in the range of 25-150 mg depending on individual portability and/or efficiency. After the second dose the subsequent supporting injections can be carried out in deltoid or a gluteus.

The maintenance dose can be adjusted monthly. At the same time it is necessary to consider long release of active component from a paliperidon of palmitate as the effect of change of a dose can be shown completely only in several months.

Admission of a dose.

Avoiding of the admission of doses. The second load dose of a paliperidon is recommended to be entered in 1 week after the first dose. If it is impossible, then it can be entered for 2 days sooner or later. Similarly, a third and the subsequent doses recommends to enter monthly, but if it is impossible, then the injection can be made for 7 days sooner or later.

If the second injection of drug of Kseplion was not made in time (one week ± 2 days), resuming of treatment depending on time which passed from the date of the first injection is recommended.

Admission of the second initial dose (term less than 4 weeks). If from the date of the first injection there passed less than 4 weeks, the patient should enter the second injection in a dose of 100 mg into a deltoid muscle as soon as possible. The third injection of drug Kseplion in a dose of 75 mg should be made in deltoid or a gluteus in 5 weeks after the first injection (disregarding time of the second injection). Further the monthly course of injections in a dose from 25 mg to 150 mg in deltoid or a gluteus depending on individual portability and/or efficiency has to be observed. 

 Admission of the second initial dose (term from 4 to 7 weeks). If from the date of the first injection of drug Kseplion there underwent from 4 to 7 weeks treatment renew introduction of two injections in a dosage of 100 mg according to the following scheme: the first injection in a deltoid muscle is done as soon as possible; in 1 week do the second injection in a deltoid muscle, then continue a monthly course of injections in deltoid or a gluteus in a dose from 25 mg to 150 mg depending on individual portability and/or efficiency.

Admission of the second initial dose (more than 7 weeks). If from the moment of the first injection of drug Kseplion there underwent more than 7 weeks treatment begin also as in case of treatment initiation with drug Kseplion.

The admission of a maintenance dose (term from 1 month to 6 weeks). After an initiation of treatment Kseplion monthly is recommended to carry out drug injections. If from the moment of the last injection there passed less than 6 weeks, then it is necessary to enter as soon as possible the next dose equal to previous. After that to administer the drug monthly.

The admission of a maintenance dose (term from> 6 weeks up to 6 months). If from the moment of the last injection of drug Kseplion there passed more than 6 weeks the following is recommended:

For the patients stabilized by a dose from 25 mg to 100 mg:

1) Do a drug injection in a deltoid muscle as soon as possible in that dose on which there took place stabilization of a condition of the patient to the admission of an injection;

2) The following injection in a deltoid muscle (the same dose) is done in a week for the 8th day;

3) Further renew a monthly course of injections in deltoid or a gluteus in a dose from 25 mg to 150 mg depending on individual portability and/or efficiency.

For patients of 150 mg stabilized by a dose:

1) As soon as possible enter a dose of 100 mg into a deltoid muscle;

2) In 1 week enter one more dose of 100 mg (the 8th day) into a deltoid muscle;

3) Further renew a monthly course of injections in deltoid or a gluteus in a dose from 25 mg to 150 mg depending on individual portability and/or efficiency.

Admission of a maintenance dose (term> of 6 months). If from the moment of the last injection of drug Kseplion there passed more than 6 months, then treatment begin again as above to start treatment is described.

Route of administration.

Kseplion is intended only for intramuscular introduction. The drug is slowly administered deeply in a muscle. Only the health worker has to carry out injections. All dose is entered for once; it is impossible to enter a dose for several injections. It is impossible to administer the drug in vessels or subcutaneously. It is necessary to avoid accidental hit in a blood vessel. For this purpose before administration of drug the piston of the syringe is delayed for check regarding hit of a needle in a large blood vessel back. If at the same time blood comes to the syringe, it is necessary to take a needle and the syringe from a muscle of the patient and to utilize them. The recommended needle size for maintaining drug Kseplion in a deltoid muscle is defined by the body weight of the patient. For patients with a body weight of ≥90 kg the long needle with the gray case from set is recommended. For patients with body weight <90 kg the short needle with the blue case from set is recommended. It is necessary to administer serially the drug in the right and left deltoid muscle.

For administration of drug Kseplion in a gluteus is recommended a long needle with the gray case from set. Injections need to be carried out to an upper outside quadrant of a buttock. It is necessary to administer serially the drug in the right and left gluteus. Simultaneous use of Paliperidon of palmitate and a paliperidon orally or a risperidona orally or parenterally was not studied. As палиперидон is the main active metabolite of a risperidon, it is necessary to consider a possibility of the additive action of a paliperidon at use of these drugs along with drug Kseplion.

Patients with an abnormal liver function. Drug use Kseplion at patients with an abnormal liver function was not studied. Proceeding from results of a research of a paliperidon for intake, for patients with an abnormal liver function easy or moderate severity of dose adjustment is not required. Drug use Kseplion at patients with disturbance of functions of a liver of heavy degree was not studied.

Patients with a renal failure. Drug use Kseplion at patients with a renal failure systematically was not studied. At patients with a renal failure of easy severity (clearance of creatinine from ≥ 50 to <80 ml/min.), Kseplion is recommended to begin drug use with a dose of 100 mg in the 1st day and 75 mg in 1 week (both injections in a deltoid muscle). After that in 1 month enter an injection in a dose of 50 mg in deltoid or a gluteus, and further change a dose from 25 mg to 100 mg depending on individual portability and/or efficiency. Kseplion is not recommended to apply at patients with a renal failure of average or heavy degree (clearance of creatinine <50 ml/min.).

Elderly patients. In general, for elderly patients with normal function of kidneys the same dose of drug Kseplion, as for younger patients with normal function of kidneys is recommended. At elderly patients function of kidneys can be reduced, and the stated above recommendations for patients with a renal failure extend to such patients.

Teenagers and children. Safety and efficiency of use of drug Kseplion at patients are younger than 18 years was not studied.

Other special categories of patients. To drug dose adjustment Kseplion depending on a floor, race of patients and smoking is not required.

Transfer from other neuroleptics. Data on transfer of patients with schizophrenia from other neuroleptics or about its use along with other neuroleptics systematically did not gather on Kseplion. For patients who never accepted peroral палиперидон either peroral or injection рисперидон portability with a peroral paliperidon or a peroral risperidon before an initiation of treatment drug Kseplion has to be investigated. In an initiation of treatment drug Kseplion the neuroleptics which were earlier applied orally can be cancelled. Kseplion it is necessary to appoint as above in the section "Route of Administration and Doses" is described. If the patient receives injection neuroleptics of the prolonged action, treatment by drug Kseplion begin with a maintenance dose at the time of the next planned injection at once. It is necessary to continue treatment by drug Kseplion once a month. The initial dose on the first week of treatment is not required.

At patients who were stabilized by various doses of drug Rispolept Konsta® suspension for intramuscular introduction of the prolonged action, equilibrium concentration of active agent can reach similar values during a maintenance therapy drug Kseplion according to the following scheme once a month:

Last dose of Rispolept Konst        Initial dose Kseplion

To 25 mg there are each 2 weeks                of 37,5 mg everyone once a month

50 mg each 2 not cases                 of 50 mg everyone once a month         

 75 mg each 2 not cases                 of 100 mg once a month

Cancellation of the previous anti-psychotic should be carried out according to the instruction on a medical use. At drug withdrawal Kseplion it is necessary to consider long release of active component. As well as in a case with other neuroleptics, it is necessary to estimate periodically need of continuation of use of prophylactics of development of extrapyramidal frustration.

Features of use:

Malignant antipsychotic syndrome.

At use of neuroleptics, including a paliperidona, development of the malignant antipsychotic syndrome (MAS) characterized by a hyperthermia, muscular rigidity, instability of the autonomic nervous system, disturbance of consciousness and increase in concentration of a kreatinfosfokinaza of blood serum is registered. Besides, can be observed a myoglobinuria (рабдомиолиз) and an acute renal failure. At emergence of the symptoms allowing to assume ZNS, all neuroleptics including Kseplion, cancel. 

Late dyskinesia.

Use of the drugs having properties of antagonists of dopamine receptors is followed by development of the late dyskinesia which is characterized by the rhythmical, involuntary movements, mainly language and/or facial muscles. At emergence of symptoms of late dyskinesia it is necessary to consider the possibility of cancellation of all neuroleptics, including Kseplion.

Hyperglycemia and diabetes mellitus.

At treatment drug Kseplion observed a hyperglycemia, a diabetes mellitus and an aggravation of already available diabetes mellitus. Establishment of interrelation between use of atypical antipsychotic drugs and disturbance of exchange of glucose is complicated by the increased risk of development of a diabetes mellitus in patients with schizophrenia and prevalence of a diabetes mellitus in the general population. Considering these factors, interrelation between use of atypical antipsychotic drugs and development of the side effects connected with a hyperglycemia it is established not completely. At all patients it is necessary to carry out clinical control on existence of symptoms of a hyperglycemia and diabetes mellitus (see the section "Side effect").

Increase in body weight.

At treatment atypical anti-psychotics observed significant increase in body weight. It is necessary to carry out control of body weight of patients.

Elderly patients with dementia.

The cross analysis of results of researches showed the increased mortality of the elderly patients with dementia receiving atypical neuroleptics, including рисперидон, арипипразол, olanzapine and кветиапин in comparison with placebo. Among the patients receiving рисперидон and placebo, mortality made respectively 4% and 3,1%.

Drug use Kseplion at elderly patients with dementia was not studied. As палиперидон is an active metabolite of a risperidon, it is necessary to consider experience of use of a risperidon. For the elderly patients with dementia accepting рисперидон the increased mortality at the patients accepting furosemide and рисперидон in comparison with the group accepting only рисперидон and the group accepting only furosemide was observed. It is not installed the pathophysiological mechanisms explaining this observation. Nevertheless, it is necessary to observe extra care at purpose of drug in such cases. Increase in mortality at the patients who are at the same time accepting other diuretics together with risperidony is not revealed. Irrespective of treatment, dehydration is the general risk factor of mortality and has to be controlled carefully at elderly patients with dementia.

Disturbances of cerebral circulation.

In placebo - controlled researches the increased frequency of disturbances of cerebral circulation (passing and a stroke), including from the death, is found in the elderly patients with dementia receiving some atypical neuroleptics, including рисперидон, арипипразол and olanzapine in comparison with placebo use.

Leukopenia, neutropenia, agranulocytosis.

The leukopenia, neutropenia and agranulocytosis were noted at use of antipsychotic means, including at drug use Kseplion. The agranulocytosis was noted very seldom during post-marketing observations. To patients, with clinically significant reduction of quantity of leukocytes in the anamnesis or drug - a dependent leukopenia / neutropenia is recommended carrying out an integrated analysis of blood within the first months of therapy, the treatment termination by drug Kseplion has to be considered at the first clinically significant reduction of quantity of leukocytes in the absence of other possible reasons. Patients with clinically significant neutropenia are recommended to be observed regarding temperature increase or emergence of symptoms of an infection and to begin treatment immediately, at emergence of such symptoms. Patients with a severe form of a neutropenia (absolute quantity of neutrophils less than 1 x 109/l) have to stop drug use Kseplion until the quantity of leukocytes is not normalized.

Venous tromboembolizm.

At use of antipsychotic drugs cases of a venous thromboembolism were noted. As the patients accepting antipsychotic drugs often have risk of development of a venous thromboembolism, all possible risk factors должныбыть are revealed to and during treatment by drug Kseplion and the warning measures have to be taken.

Parkinson's disease and dementia with Levi's little bodies.

The doctor has to compare risk and advantage of use of neuroleptics, including Kseplion, at patients with Parkinson's disease or dementia with Levi's little bodies as at both of these categories of patients the risk of development of the malignant antipsychotic syndrome (MAS) and risk of hypersensitivity to neuroleptics can be increased. Manifestations of hypersensitivity can include confusion of consciousness, obtusion of painful sensitivity, instability of a pose with frequent falling, and also extrapyramidal symptoms.

Priapism.

There are data on ability of the drugs having properties of alpha adrenoblockers to cause a priapism. The priapism is registered within post-marketing control of use of a paliperidon.

Antiemetic action.

In preclinical trials of a paliperidon antiemetic action is revealed. Emergence of this effect in the patient can mask signs and symptoms of overdose of some drugs or, for example, such states as impassability of intestines, a syndrome to Reja or a brain tumor.

Introduction.

At intramuscular introduction it is necessary to show care in order to avoid accidental hit of drug in a blood vessel.

Influence on driving of the car and work with mechanisms.

Kseplion can break performance of the actions demanding concentration of attention and speed of psychomotor reactions and can influence sight. Therefore patients should recommend not to manage vehicles and moving mechanisms, their individual sensitivity will not be established yet.

Side effects:

The majority of the undesirable side reactions (USR) were weak or moderately severe. 

The undesirable reactions observed at patients are provided below. Frequency of undesirable reactions was classified as follows: very frequent (≥10%), frequent (≥1% and <10%), infrequent (≥0,1% and <1%), rare (≥0,01% and <0,1%) and very rare (<0,01%).

Infections:

- frequent – upper respiratory tract infections;

- infrequent – an acariasis, bronchitis, an inflammation of a hypodermic fatty tissue, an infection of an ear, an eye infection, flu, an onychomycosis, pneumonia, respiratory infections, sinusitis, hypodermic abscess, tonsillitis, infections of an urinary system.

From immune system:

- infrequent – hypersensitivity.

Disturbances from circulatory and lymphatic system:

- infrequent – a neutropenia, reduction of quantity of white blood cells;

- rare – thrombocytopenia;

- very rare – an agranulocytosis.

Disturbances from endocrine system:

- rare – inadequate secretion of antidiuretic hormone.

Metabolic disturbances:

- frequent – increase in body weight;

- infrequent – anorexia, a hyperglycemia, a loss of appetite, increase in appetite, decrease in body weight, a polydipsia, a diabetes mellitus;

- rare – a hypoglycemia;

- very rare – diabetic ketoacidosis, water intoxication.

Psychiatric frustration:

- very frequent – sleeplessness, excitement;

- frequent – nightmares, concern;

- infrequent – a depression, a sleep disorder, manias.

Disturbances from a nervous system:

- very frequent – a headache;

- frequent - an akathisia, dizziness, extrapyramidal symptoms, drowsiness, parkinsonism (including an akineziya, a bradykinesia, rigidity as "cogwheel", hypersalivation, extrapyramidal symptoms, a deviation of a glaberalny reflex, muscular rigidity, constraint in muscles, a skletno-muscular immovability);

- infrequent – a lack of coordination, cerebrovascular disturbances, spasms (including epileptic spasms), absent-mindedness of attention, postural dizziness, a dysarthtia, dyskinesia (including an athetosis, a chorea, a choreoathetosis, disturbance of the movement, muscular contractions, clonic spasms), dystonia (including a nictitating spasm, a neck spasm, эмпростотонус, a spasm of the person, a hypertension, a laryngospasm, involuntary muscular contractions, a myatonia, the movements of an eyeglobe, an opisthotonos, an orofaringealny spasm, плеврототонус, a cynic spasm, a tetany, a glossolysis, a glossospasm, a wryneck, a sudorozhnoyestiskivaniye of jaws), a gipoesteziya, paresthesia, a psychomotor hyperactivity, a syncope, heavy dyskinesia, a tremor.

Ophthalmologic disturbances:

- infrequent – a xerophthalmus, increase in dacryagogue, an ocular hyperemia, the involuntary movement of an eyeglobe, an illegibility of visual perception.

Disturbances from an acoustic organ and balance:

- infrequent – вертиго, ear pain.

Disturbances from cardiovascular system:

- frequent – increase in arterial pressure;

- infrequent – an atrioventricular block, bradycardia, disturbance of conductivity, disturbance on the electrocardiogram, increase in an interval of QT on the electrocardiogram, heartbeat, a syndrome of postural orthostatic tachycardia, a sinus arrhythmia, tachycardia, fibrillation of auricles, orthostatic hypotension;

- rare – a deep vein thrombosis;

- very rare – an embolism of a pulmonary artery.

Disturbances from respiratory system:

- infrequent – cough, диспноэ, nasal bleeding, a nose congestion, pain in pharyngeal and guttural area, a congestion of respiratory tracts, goose breathing, a congestion of lungs;

- very rare – an apnoea syndrome in a dream.

Gastrointestinal disturbances:

- frequent – pain in an upper part of a stomach, a lock, diarrhea, dryness of a mucous membrane of an oral cavity, nausea, a dentagra, vomiting, discomfort in a stomach;

- infrequent – dyspepsia, a dysphagy, an incontience a calla, a meteorism, a gastroenteritis, a paraglossa, a dysgeusia;

- rare – pancreatitis.

Disturbances from gepatobiliarny system:

- very rare – jaundice.

Disturbances from a musculoskeletal system and connecting fabric:

- frequent – extremity pain, skeletal and muscular pain;

- infrequent – an arthralgia, a dorsodynia, constraint of joints, swelling of joints, muscular spasms, neck pain.

Disturbances from skin:

- infrequent – an acne, a xeroderma, eczema, an erythema, гиперкератозис, urticaria, an itch, rash, an alopecia;

- rare – an angioedema.

Disturbances from an urinary system:

- infrequent – a dysuria, a pollakiuria, an urine incontience;

- rare – a mochevyvedeniye delay.

Disturbances from reproductive system and mammary glands:

- infrequent – an amenorrhea, a galactorrhoea, a gynecomastia, sexual dysfunction, disturbances of an ejaculation, erectile dysfunction, vaginal allocations;

- very rare – a priapism.

Influence on the course of pregnancy, puerperal and perinatal states:

- very rare – a withdrawal at newborns.

Others:

- frequent – asthenic frustration, weakness, local reactions (pain, an itch, consolidation in the place of an injection), infrequent – discomfort in a breast, the fever, a face edema, gait disturbance, consolidation in the place of a prick, swelled (including generalized hypostasis, peripheral hypostasis, soft hypostasis), thirst, the increased body temperature;

- rare – a hypothermia, abscess in an injection injection site, an inflammation of hypodermic cellulose in an injection injection site, a hematoma in an injection injection site;

- very rare – a cyst in an injection injection site, a necrosis in an injection injection site, an ulcer in an injection injection site.

Changes of laboratory indicators:

- infrequent – increase in activity of a gamma glutamiltransferaza, increase in activity of enzymes of a liver, increase in activity of transaminases, increase in concentration of cholesterol in blood, increase in concentration of triglycerides in blood, a hyperglycemia.

Interaction with other medicines:

Paliperidon can increase Q-T interval therefore it should be combined with care with other medicines increasing Q-T interval (antiarrhytmic medicines, including quinidine, procaineamide, Amiodaronum, соталол; antipsychotic medicines (Chlorpromazinum, thioridazine); antibiotics, including гатифлоксацин, moxifloxacin.

As Paliperidona palmitate is hydrolyzed to a paliperidon, at assessment of a possibility of medicinal interaction it is necessary to consider results of researches of a paliperidon for intake.

Ability of drug Kseplion to influence other drugs.

It is not expected that палиперидон will show clinically significant pharmacokinetic interaction with drugs, metaboliziruyemy isoenzymes of system of P450 cytochrome. Researches with use of microsomes of a liver of the person of in vitro showed what палиперидон significantly does not weaken metabolism of substances isoenzymes of CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. Therefore it is not expected that палиперидон will reduce clinically significantly clearance of drugs, metaboliziruyemy these isoenzymes. Also it is not expected that палиперидон will show properties of the inductor of isoenzymes since in the researches in vitro палиперидон did not induce activity of isoenzymes of CYPA2, CYPC19 or CYP3A4. Paliperidon in high concentration is weak inhibitor of the R-glycoprotein. However there are no these in vivo in this respect, and the clinical importance of this phenomenon is unknown.

Considering action of a paliperidon on TsNS, it is necessary to apply with care Kseplion in a combination with other medicines of the central action and alcohol. Paliperidon can weaken effect of a levodopa and agonists of dopamine receptors.

Because of ability of drug Kseplion to cause orthostatic hypotension the additive strengthening of this effect at drug use Kseplion together with other drugs having such ability can be observed.

The concomitant use of a peroral paliperidon in a dosage of 12 mg once a day and tablets of sodium of a divalproyeks of the prolonged action (in a dosage of 500 - 2000 mg once a day) does not influence Valproatum pharmacokinetics. Pharmacokinetic interaction between drug Kseplion and lithium is improbable.

Ability of other drugs to influence Kseplion.

Paliperidon is not substrate of isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5. It allows to assume weak probability of interaction with inhibitors and inductors of these isoenzymes. Though the researches in vitro show a possibility of the minimum participation of CYP2D6 and CYP3A4 in metabolism of a paliperidon, there are no data that these enzymes can play an essential role in metabolism of a paliperidon of in vitro or in vivo now. The researches in vitro demonstrate to what палиперидон is P-glycoprotein substrate.

Paliperidon in limited degree is metabolized by CYP2D6 isoenzyme. In a research of interaction of a paliperidon for intake with active CYP2D6 inhibitor paroksetiny at healthy volunteers clinically significant change of pharmacokinetics of a paliperidon is not revealed.

Reception of a paliperidon with long release of active component (once a day) orally along with carbamazepine (200 mg 2 times a day) led to decrease in average Cmax and AUC of a paliperidon approximately for 37%. This decrease is substantially caused by increase in renal clearance of a paliperidon by 35% probably due to activation of a renal P-glycoprotein carbamazepine. Very small reduction of amount of the drug removed through kidneys in not changed look allows to assume that carbamazepine only poorly influences on mediated through metabolism in a liver or bioavailability of a paliperidon. At the beginning of use of carbamazepine the drug dose Kseplion should be reconsidered and, if necessary, to increase. On the contrary, at carbamazepine cancellation the drug dose Kseplion should be reconsidered and, if necessary, to reduce.

Paliperidon at a physiological rn is a cation and is generally brought in not changed look through kidneys – a half by filtering, and a half – by active secretion. Simultaneous use of Trimethoprimum which inhibits system of active transport of cations in kidneys did not influence pharmacokinetics of a paliperidon.

At co-administration of a peroral paliperidon of the prolonged action in a dosage of 12 mg once a day and tablets of the prolonged effect of sodium of a divalproyeks (2 tablets on 500 mg once a day) increase in Cmax and AUC of a paliperidon by 50% was observed, it is probable as a result of increase in absorption of drug at oral administration. As considerable influence on the general clearance was not observed, clinically significant interaction between divalproyeksy sodium, a tablet of a long vysvodobozhdeniye and drug Kseplion is not expected. It is necessary to consider the possibility of reduction of a dose of drug Kseplion at co-administration with Valproatum on the basis of clinical assessment of the patient. Interaction researches with drug Kseplion were not conducted.

Pharmacokinetic interaction of lithium and paliperidon a little possibly.

Drug use Kseplion together with risperidony.

Drug use Kseplion together with risperidony was not studied. As палиперидон is an active metabolite of a risperidon, at simultaneous use of drug Kseplion and a risperidona it is necessary to consider increase in concentration of a paliperidon in a blood plasma.

Contraindications:

Hypersensitivity to a paliperidon or any component of drug. As палиперидон is an active metabolite of a risperidon, Kseplion is contraindicated to patients with the known hypersensitivity to a risperidon.

About ostorozhnosty.

Orthostatic hypotension. Having activity of alpha adrenoblocker, палиперидон can cause orthostatic hypotension in some patients. Kseplion it is necessary to apply with care at patients with cardiovascular diseases (for example, heart failure, a heart attack or ischemia of a myocardium, disturbance of cordial conductivity), the disturbances of cerebral circulation or states contributing to a lowering of arterial pressure (for example, dehydration, reduction of volume of the circulating blood, use of hypotensive drugs).

Spasms. As well as other neuroleptics, Kseplion it is necessary to apply with care at the patients having in the anamnesis of a spasm or other states at which the convulsive threshold can decrease.

Regulation of body temperature. Using neuroleptics connect deterioration in ability of an organism to reduce body temperature. It is recommended to show care at purpose of drug Kseplion to patients who can be affected to the strong exercise stress increasing body temperature, for example, high temperature of the environment, influence of drugs with activity of m cholinolytics, and also to dehydration.

Q-T interval. As well as in case of other neuroleptics, the patients having arrhythmia or inborn lengthening of an interval of Q-T in the anamnesis, or accepting the drugs extending Q-T interval should show care at purpose of drug Kseplion. Considering action of a paliperidon on the central nervous system (CNS), it is necessary to apply with care Kseplion in a combination with other medicines operating on TsNS and alcohol. Paliperidon can weaken effect of a levodopa and agonists of dopamine.

It is necessary to show care at purpose of drug Kseplion to elderly patients with dementia, to patients with Parkinson's disease or dementia with Levi's little bodies (see the section "Special Instructions").

Overdose:

As Kseplion is intended for introduction by medics, the probability of its overdose by patients is small.

Symptoms.

In general, the expected signs and symptoms correspond to strengthening of the known pharmacological action of a paliperidon, i.e. drowsiness, block, tachycardia, a lowering of arterial pressure, lengthening of an interval of Q-T, extrapyramidal symptoms. Poliformny ventricular tachycardia like "pirouette" and fibrillation of ventricles were noted at overdose of a peroral paliperidon. In case of acute overdose it is necessary to consider a possibility of receiving several drugs by patients.

Treatment.

At assessment of need for treatment and recovery of patients it is necessary to consider long release of active agent and a big elimination half-life of a paliperidon. The specific antidote for a paliperidon does not exist. It is necessary to carry out the general supporting measures, to provide and maintain passability of respiratory tracts, sufficient ventilation of the lungs and saturation of blood by oxygen. It is necessary to begin immediately control of function of cardiovascular system, including continuous monitoring of an ECG for detection of possible arrhythmia. In case of a lowering of arterial pressure of blood and a circulator collapse it is necessary to undertake the appropriate measures, for example, intravenous administration of solutions and/or sympathomimetics. At development of heavy extrapyramidal symptoms use anticholinergic drugs. It is necessary to control carefully a condition of the patient before his recovery.

Storage conditions:

At a temperature not above 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Suspension for intramuscular introduction of the prolonged action, 25 mg / 0,25 ml, 50 mg / 0,50 ml, 75 mg / 0,75 ml, 100 mg / 1мл, 150mg/1,5 ml On 0,25, 0,50, 0,75, 1,00, 1,50 ml of drug in the syringe from tsiklolefinovy copolymer. 2 needles for intramuscular injections are included in the package of drug (in deltoid and a gluteus).